Autoimmunity and emphysema and risk of osteoporosis in smokers

吸烟者的自身免疫和肺气肿以及骨质疏松症的风险

基本信息

批准号：
9916794
负责人：
JESSICA BON
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916794
关键词：
Age Alveolar Macrophages Antibodies Autoantibodies Autoimmune Process Autoimmune Responses Autoimmunity Binding Binding Proteins Biological Assay Biological Markers Bone Density Cachexia Cause of Death Cells Chronic Obstructive Airway Disease Data Dentin Diagnostic radiologic examination Disease Disease Progression Endoplasmic Reticulum Enzyme-Linked Immunosorbent Assay Female Foundations Fracture Future Goals Heat shock proteins High Prevalence Human Immune Targeting Immune response Immunoglobulin G Immunohistochemistry Immunologic Markers Immunologics Immunomodulators In Vitro Incidence Inflammation Mediators Inflammatory Investigational Therapies Link Literature Longitudinal cohort Lung diseases Measurement Measures Mediating Molecular Molecular Chaperones Morbidity - disease rate NF-kappa B Natural History Osteoclasts Osteoporosis Osteoporosis prevention Participant Pathogenesis Pathogenicity Pathologic Patient Selection Patients Physical activity Physiological Population Prevalence Prevention strategy Process Production Proteins Pulmonary Emphysema Reaction Time Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Risk stratification Roentgen Rays Role Scanning Series Smoker Smoking Status Stains Steroids Testing United States Variant Woman X-Ray Computed Tomography airway obstruction biological adaptation to stress bone bone resorbing activity bone turnover clinically significant cohort cytokine endoplasmic reticulum stress falls follow-up glucose-regulated proteins improved insight male men mortality novel nuclear factors of activated T-cells osteoporosis with pathological fracture patient population physical inactivity precursor cell public health relevance pulmonary function response screening guidelines smoking-related lung disease targeted agent tartrate-resistant acid phosphatase time interval tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Low bone mineral density (BMD) has been linked to chronic obstructive pulmonary disease (COPD) independent of traditional osteoporosis risk factors including steroid use, cachexia, and decreased physical activity. Although the increased prevalence of osteoporosis contributes to morbidity and mortality in COPD patients, little is known regarding indications for BMD assessment or osteoporosis mechanisms in this susceptible population. The rate of BMD loss is an independent risk factor for fracture. Yet, cross-sectional dual x-ray absorptiometry (DXA) assessment of BMD provides no information about rate of BMD decline. Immunologic alterations contribute to the pathogenesis of both COPD and osteoporosis but the role of autoimmunity in COPD-related osteoporosis has not been studied. An independent association between emphysema and low BMD has been supported by the literature, but the mechanism for this association is also unknown. This project's overall goal is to study how specific autoimmune processes relate to concurrent emphysema progression and accelerated BMD decline in male and female smokers with lung disease. This goal will be accomplished through extension to six years of an already established longitudinal cohort with pre- existing baseline and two-year assessments of BMD, radiographic emphysema, pulmonary function, and autoimmune biomarker levels. The association of an autoimmune biomarker, anti-glucose regulated protein 78 (GRP78) IgG, with emphysema progression, measured by quantitative CT scan, and BMD loss, measured by serial DXA, over the six-year time interval will be studied in smokers with emphysema or airflow obstruction. A series of in vitro osteoclast studies will be performed to assess the effect of autoantibodies to GRP78, an endoplasmic reticulum (ER) chaperone protein intimately involved in the ER stress response, on osteoclast formation, proliferation, and activity. The findings from this project will identify criteria for smokers at risk of accelerated BMD loss in whom early and serial measurements of BMD may be warranted, provide insight into pathogenic mechanisms linking emphysema and osteoporosis, and provide novel targets for osteoporosis prevention and treatment strategies in patients with COPD.

描述（由适用提供）：低骨矿物质密度（BMD）与慢性阻塞性肺部疾病（COPD）有关，与传统骨质疏松症的危险因素无关，包括立体声使用，卡希克西亚和增加体育活动。尽管骨质疏松症的患病率增加有助于COPD患者的发病率和死亡率，但关于该易感人群的BMD评估或骨质疏松机制的指示知之甚少。 BMD损失率是骨折的独立危险因素。然而，BMD的横截面双X射线绝对测定法（DXA）评估没有提供有关BMD下降率的信息。免疫学改变有助于COPD和骨质疏松症的发病机理，但是自身免疫性在与COPD相关的骨质疏松症中的作用尚未研究。文献支持了肺气肿和低BMD之间的独立关联，但是该关联的机制也未知。该项目的总体目标是研究特定的自身免疫过程如何与肺部和女性吸烟者同时发生的肺气肿进展以及BMD加速下降有关。该目标将通过扩展到已经建立的纵向队列的六年来实现，对BMD，放射线肺气肿，肺功能和自身免疫性生物标志物水平进行了预先现有的基线和两年评估。自身免疫性生物标志物，抗葡萄糖调节蛋白78（GRP78）IgG与肺气肿进展，通过定量CT扫描测量的肺气肿进展，通过串行DXA测量的BMD损失，在六年的时间间隔中，将在具有孔隙症或空气流量的吸烟中研究。将进行一系列体外破骨细胞研究，以评估自身抗体对GRP78的影响，GRP78是内质网（ER）伴侣蛋白密切参与ER应激反应，对破骨细胞形成，增殖，增殖和活性的影响。这个项目的发现将确定有加速BMD损失风险的吸烟者的标准，其中可能有必要对BMD进行早期和串行测量，提供有关将肺气肿和骨质疏松症联系起来的致病机制，并为COPD患者的骨质疏松症预防和治疗策略提供新的目标。